Acute vascular occlusions, ischemia and infarction are common medical concerns. Acute Myocardial Infarction (“AMP”) subsequent to coronary thrombotic occlusion in particular is the leading cause of death in North America and Europe, and Acute Ischemic Stroke subsequent to cerebral arterial thrombotic occlusion is the third leading cause of death, and a leading cause of serious disability. Current first line treatment of thromboses in the acute phase when the patient reaches professional care (in the case an invasive catheter based treatment option is not readily available—which is often the case, especially in rural areas) is typically by intravenous introduction of thrombolytics, or a combination of drugs such as heparin, aspirin and/or GP 2b 3a platelet inhibitors to dissolve the blood clot. Intravenous and oral nitrates may also be introduced in order to dilate the culprit coronary or other vessel, which usually has a degree of spasm associated.
Thrombolytic drug treatment does not, however, have a high success rate in treatment of heart attack or acute ischemic stroke. The success of systemically delivered IV drug therapy in increasing reperfusion rates in the treatment of ST elevation AMI is discussed in the following publications:
1.) American Heart Association, Satellite Symposium 73rd Scientific Session, St. Michael's Review, New Orleans, La.; Nov. 11, 2000.
2.) Francis W M.D., “Ultrasound—Enhanced Thrombolysis.” Echocardiography: A. Jrnl. of CV Ultrasound & Allied Tech. Vol. 18, No. 3, 2001. pp 239-246.
3.) Sanborn T et al., “Impact of Thrombolysis lntra-aortic Balloon Pump Counter pulsation and their Combination in Cardiogenic Shock Complicating Acute Myocardial Infarction.”, SHOCK REGISTRY JACC, 36 (3) Suppl. A. 2000, 1123-9. The American Heart Association, Satellite Symposium 73rd Scientific Session, St. Michael's Review reported reperfusion rates (i.e. TIMI 3 flow @ 60-90 minutes) with standard thrombolytic therapy varying between 50 and 63%.
Francis reported that lytic therapy fails to achieve any reperfusion (at all) in up to 20% of patients.
Success with drug based reperfusion treatment and in-hospital survival declines markedly when the patient becomes hemodynamically unstable or enters cardiogenic shock, which is the leading cause of in-hospital deaths from MI in North America. Sanborn et al. report 63% in-hospital mortality despite the use of thrombolytic therapy.
In the case of ST elevation Acute Myocardial Infarction, when noninvasive drug treatment (i.e. systemically introduced IV thrombolysis) to achieve reperfusion fails, invasive catheter based techniques such as Percutaneous Coronary Intervention (“PCI”) are employed. Where possible (i.e. when a cathlab is reachable within 90 minutes when a patient presents to medical care), PCI is chosen as a direct measure, whereby a coordination of the immediate use of blood thinning agents may be first established in the field while en route to a cardiac catheterization laboratory where intervention can be performed. A disadvantage of invasive treatment for acute thrombotic occlusions (while very successful) is the infrastructure required, particularly the cardiac “cathlab” requiring substantial equipment and staff. Such infrastructure is not readily accessible in hospitals world wide, and even when available, there is a significant time requirement to coordinate and set up equipment and personnel. Due to the lack of immediate availability of cathlabs, patients, often unstable, must be transported and/or wait for the cathlab team to assemble. These difficulties result in a delay in treatment increasing myocardial necrosis, and reducing the likelihood of a successful and timely reperfusion. There are similarly a lack of invasive neurological treatment centers enabling direct intra-coronary thrombolysis for treatment of acute ischemic stroke, hence IV thrombolysis via TPA remains the gold standard in most centres throughout North America and Europe.
Treatment systems utilizing noninvasive vibration in the low frequency ultrasonic range (“LFUS” e.g. 20 kHz-100 kHz) have been employed as an adjunct to systemically delivered IV thrombolysis including coronary and cerebral thrombolysis, in attempting to overcome these disadvantages. The LFUS wave form provides mechanical agitation via cavitation and acoustic streaming to the blood within the culprit vasculature wherein a blood clot resides, thereby encouraging disruption of the clot and increased permeation of the drug into the clot to accelerate reperfusion.
LFUS to disrupt thromboses and assist thrombolysis, has however, only shown effectiveness in research applications (i.e. animal studies), for the treatment of relatively superficial thromboses, where the exact, fixed location of the blood clot was already known to the investigator. LFUS wave forms (which deliver low amplitude micro displacements which are imperceptible to a patient) offer no assurance of therapeutic ultrasonic penetration to reach a blood clot within a human body in a practical application, without, for example, the establishment of a viable acoustic energy delivery window and targeting via direction of an application probe (i.e. as in ultrasonographic imaging), which takes intelligible application of force and angulation of the probe against a patient's skin via a skilled operator. The subsequent resultant need for high skill to direct a LFUS application makes such a therapy a poor candidate for emergency cases where a skilled treatment operator would rarely be available. A non-directed LFUS treatment (without a skilled imaging approach) in particular, is poorly suited towards human coronary applications as the human heart is a relatively deep structure, is located variably within the thoracic cavity, and the blood clot is a hidden, moving target located beneath highly attenuating anatomic structures such as lung, fat and dense intercostal muscle which does not transmit ultrasound.
Thompson, T. et al in U.S. patent application No. 20020049395-2002, disclose the emergency application of a non-directed LFUS treatment in conjunction with thrombolytic therapy in response to Acute MI in humans, wherein LFUS is delivered in a nonspecific manner to a patients skin surface through a liquid cooling medium without intelligible placement and direction of the ultrasonic source through a confirmed ultrasonic penetrating window. As stated this method is sub-optimal as it does not insure adequate penetration of the therapeutic signal, and no proof is provided that this style of technique will show a clinical benefit in humans. Further examples of this kind of noninvasive LFUS treatment for vascular thromboses are disclosed in U.S. Pat. Nos. 6,126,619, 5,713,831, 5,879,314, 6,126,619, and 6,398,772; as well as in U.S. patent application Nos. 20020082529, 20020107473, 20020072691, 20020055693, 200200726690 and 20020091339. The use of transcranial LFUS (300 kHz) has been shown to be ineffective and dangerous (causing intra-cerebral bleeding) in a recent clinical trial treating acute ischemic stroke victims (TRUMBI Trial).
Non-invasively delivered ultrasonic treatment systems directed by skilled medical imaging techniques to disrupt an undesirable target (including thromboses), have been disclosed in numerous articles and publications.
Carter and Siegel in U.S. Pat. No. 5,509,896 and U.S. Pat. No. 5,695,460 respectively, disclose an externally applied LFUS treatment probe placed in direct contact with a patient's skin (with optional means to enable “directing” or “focusing” of the LFUS wave form towards the area or volume targeted) to improve emergency thrombolysis, including coronary thrombolysis. A thrombolytic agent and/or cavitating micro bubble solution is preferably introduced by a catheter placed “proximate” the site of the vascular occlusion, to ensure effectiveness of the treatment system. The requirement of high skill (both in directing the treatment probe, and in the invasive procedure of introducing a catheter) is not ideal (nor preferable) for first line therapy applications in the field or in the emergency room. Furthermore the probe contact will typically overheat and cause burning of the patient's skin. In treatment of acute ischemic stroke, the use of Transcranial Doppler (TCD)—a skilled diagnostic ultrasound imaging procedure in the MHz ranges—has reported some preliminary success in accelerate cerebral IV thrombolysis particularly with microbubbles, but again the need for a highly skilled approach to administer the therapy is not ideal for treatment of emergency conditions, and is rarely available in a practical setting. Further, there are some reports that TCD does not carry enough power to prospectively enhance thrombolysis when emitted through the cranium, hence casting doubt on the prospective long term use of this therapy.
Lithotriptic style techniques such as in U.S. Pat. Nos. 5,065,741, 5,207,214, 5,524,620, 5,613,940, 5,725,482, 6,068,596 and U.S. patent application Ser. No. 2004/0006288 A1 (which employ use of externally imparted focused ultrasonic waves or ultrasonic shock waves directed by an imaging modality to disrupt an internal target including thromboses) have also been disclosed. This style of therapy (while common in the treatment of kidney stones and the like) has not gained acceptance in the emergency treatment of acute vascular occlusions or thrombotic occlusions, probably because thrombotic lesions are difficult (if not impossible) to conveniently image, and these style of applications are inexpedient for use as they require advanced training, a controlled environment, calculations, and specialized equipment to employ. Furthermore, lithotriptic systems and other focused wave therapy techniques are generally limited to treatment of stationary targets within the human body, hence applications to the coronary arteries (such as in the acute treatment of coronary thrombotic lesions) cannot prospectively be performed.
Low frequency mechanical vibration treatment systems have been considered in the invasive treatment of thrombotic occlusions via catheter based techniques. U.S. Pat. No. 6,287,271 to Dubrul et al., for example, discloses a low-frequency (1-1000 Hz) vibrating catheter drug delivery system resulting in 68% lysing when placed proximally to an artificial clot in a test tube with the drug Urokinase, versus 4.5% lysing with Urokinase treatment alone. As stated above, this system is invasive, and thereby requiring great specialized skill and equipment to introduce a catheter directly to the thrombosis site, and thus has no utility as a first line measure in the field or in emergency room cases.
Generally non-invasively delivered low frequency vibration or percussion in the sonic to infrasonic ranges has received little focus in the field of treatment of acute vascular occlusions, ischemic events or blood flow disturbances.
Cardio Pulmonary Resuscitation (“CPR”), which is essentially high displacement amplitude compressional wave energy of 1.5 Hz (i.e. very low frequency vibration), was paired used successfully in conjunction with coronary thrombolysis in cases of known acute myocardial infarction which had deteriorated and a poor outcome was otherwise imminent. These cases were reported by Tiffany et al. in “Bolus Thrombolytic Infusions During CPR for Patients With Refractory Arrest Rhythms: Outcome of a Case Series” (Annals of Emergency Medicine, 31:1, January 1998, 134-136). This medical method, which was designed to sustain the life of the patient conjointly with the deliverance of thrombolysis (and not to act as an adjunct to thrombolysis per se), is limited to cardiac arrest situations, and the manual nature of the application of high displacement amplitude, mechanical energy by human hand would be labor intensive, potentially tiresome to an operator, and would eventually cause undue harm to a patient if delivered for sustained periods.
Wobser, E et al. in an article “Intragastral Disintegration of Blood Coagula by Mechanical Vibration” in Endoscopy 10, 1978, 15-19; discloses a 50-500 Hz “flexural electromagnetic resonator” for insertion into the stomach for disruption of “big blood coagula” in order to facilitate endoscopic examination in GI bleeds. Furthermore, Lee in U.S. Pat. No. 5,676,637 discloses a low frequency vibratory probe for insertion in the anus to dissolve venous thromboses to improve blood circulation in the treatment of hemorrhoids. Neither system is directed towards treatment of acute vascular blockages or emergency blood flow disturbances, and neither instrument is configured to enable effective penetration through a significantly attenuating barrier such as the chest wall or other external body surface.
Matsuura in U.S. Pat. No. 6,424,864 B1 discloses an all purpose wave therapy system (i.e. applying electric, electromagnetic and/or acoustic waves) for treatment of a plurality of ailments ranging from depression, to rheumatism, to infertility, to poor blood circulation in the hands and feet. In one disclosed embodiment, sound waves generated through one of a sonic platform apparatus or set of head phones enables acoustic therapy to the body (or “cuticle”, or “ears”) of a user in contact with the apparatus. The '864 patent describes a low intensity, dissipated therapeutic system of acoustic and electromagnetic wave transmission to a user, and is thereby not suitable to emergency disruptive and agitative applications wherein the impartation of highly concentrated external percussive force to predetermined or selected application sites is required to ensure therapeutic penetration and effectiveness. Furthermore, this system is not prescribed towards the treatment of acute vascular occlusions or ischemic events, hence there are no methods by which these particular applications could be performed. Randoll in U.S. Pat. No. 6,579,251 B1 discloses a low frequency oscillatory device for the treatment of a plurality of ailments including “micro circulation disorders”, employing a rotating eccentrically mounted treatment head which effectively delivers (when rotating) oscillatory skin displacements of between 4 to 7 mm at a frequency of 5-25 Hz to its user. The '251 patent mimics patient “tremors” to drive sequestered fluids through the valved systems of the veins and lymphatics to clear tissue spaces. Such rotating head devices are not designed nor intended for the emergency treatment of acute blood flow disturbances, and are energy inefficient as the forces of vibration are directed tangentially to the skin surface.
Endo, Y in GB2167961 discloses a bed (or mattress) sheet with a plurality of vibrating members to be applied to the body surface of a user while sleeping, for several uses ranging from reduced “sleep latency” to the prevention of “interruption in blood circulation”. The '961 patent Is not directed to emergency applications or response to ischemic events, and the vibration disclosed is ineffectual as it is of low amplitude and cannot be concentrated to a particular body part afflicted.
Cossone, A. et al. in PCT Appl. WO 02/0782 A2, and U.S. Pat. No. 6,500,134 B1 discloses a water-bath vibrating palliative, therapeutic system, with an optimal frequency of 600 Hz to generally improve coronary artery circulation in chronic cases. This water bath method is not designed (and is impractical) for use in the field and prospectively for heart attack or acute cases, and the water to skin vibrational coupling is energy transmission inefficient, of low amplitude, and does not enable focusing of treatment to key area's upon the chest wall or other body part which would confer maximum benefit.
Nagy in European Patent Appl. No. 0429109 B1 and U.S. Pat. No. 5,291,894 discloses a loud speaker system operational to generate acoustic waves (i.e. sound waves through air) in the 1-1000 Hz and 20 Hz-20 kHz range respectively, for the chronic degenerative treatment of vasoconstrictions resulting in poor circulation and stasis to the limbs of a patient. Nagy also names, in short, the optional use of a “piezoelectric element” which may alternatively be placed in direct contact against the body part treated. Sound waves through air are a highly inefficient means for delivering mechanical energy to the human body (i.e. the forces produced to the skin surface treated would be negligible), and there is no proof provided that this style of therapy would assist blood circulation in acute or chronic cases. Similarly “piezoelectric elements” (which are generally used to emit micro displacements in the ultrasonic ranges), are not operable to independently generate high displacements under load (i.e. in the low frequency ranges), hence cannot supply (prospectively) the agitative percussive force or mechanical energy required to ensure therapeutic penetration and effective treatment in emergency thrombotic applications which are often deeply situated.
Sackner in U.S. patent application No. 20020103454 discloses a “vibrating” “reciprocating movement platform” or bed which oscillates in a to and fro motion (i.e. in the head to foot direction), delivering “external pulses” to a human body in the frequency range of 0.25-6 Hz, for a plurality of applications including improving blood circulation in chronic and acute cases. The '454 patent application invokes hemodynamic forces or “pulses” by virtue of the accelerations and deceleration's of the movement platform which purportedly instill sheer stresses from blood to endothelium of the vasculature, which is known to invoke the liberation of endogenous “beneficial mediators” such as t-PA, EDRF, and Nitric Oxide (all of which are of assistance in the improvement of blood flow and prophylaxis to disease). Whole body “vibration” methods such as Sackner describes are not well suited for treatment of acute thrombotic lesions or emergency blood flow disturbances as relatively small (or insignificant) localized forces to the targeted vascular regions themselves are generated. Furthermore, the oscillations emitted are lower than the resonance frequency of the heart within the thoracic cavity, hence the vibratory effect to the heart (and coronaries) would be even further diminished in cardiac applications. Finally the treatment method invariably also shakes the patient's head which is potentially dangerous and inappropriate if the treatment system where ever to be used conjointly with thrombolytic therapy.
Jap. Pat. No. JP 8,089,549 (“549”) to Koiwa and Honda discloses a noninvasive 50 Hz diastolic timed chest wall vibrator treatment system via a singular mechanical probe to skin coupling interface to treat cardiac ischemia. The '549 patent increases coronary blood flow to stable patients with known coronary artery narrowings, through a prescribed method of applying vibration specifically timed to the diastolic phase of the cardiac cycle via a hand held unit applied to the chest wall in a low amplitude, comfortable manner (i.e. such that the patient “experiences no pain”). Koiwa teaches that diastolic timed vibration relaxes the myocardium (which is particularly stiff in ischemic states), allowing it to perfuse more efficiently and thereby assist blood perfusion to the ischemic heart.
The '549 patent is not directed to the treatment of emergent coronary incidents or acute thrombotic events, hence there are inherent limitations to the disclosed system. For example, the disclosed single probe to skin coupling is a sub-optimal means of vibration to chest wall transmission and penetration, there is no provision for the delivery of vibration at high amplitude to ensure therapeutic penetration (without for example a skilled imaging or monitoring system), and the timed application of vibration limits its effectiveness as there is no vibration during systole. The comfort level of the patient, and timing of vibration specific to diastole, is of lesser importance (and in fact limiting) when the key point of the therapy is to agitate and disrupt a thrombus, as well as to encourage the mixing of drugs into the thrombus. Furthermore, complex monitoring and processing means via an electrocardiographic trigger are required to effect cardiac phase controlled varying vibration, thus the treatment system is somewhat awkward and difficult to use prospectively in emergency cases.
Low frequency vibrators or percussive devices of high power and displacement enablement are well known (e.g. for massage and mobilization of pulmonary congestions), but have found no utility in the treatment of acute vascular occlusions or response to ischemic events. These devices (such as the Mini Pro 2 Thumper™, Homedics Professional Percussion Massager, and the “Deep muscle stimulator device” disclosed in U.S. Pat. No. 6,682,496), while of potential employment to the current specification, are not ideal as they are equipped with one, non-adjustable high displacement amplitude setting, so their vibrations may be either too strong or too weak depending on the body surface and tolerance level of the patient treated. Also, such devices are known to quickly overheat and dampen oscillations when placed under load, which greatly diminishes their overall penetration power and application time.
Vibration devices with incrementally selectable force or power control (i.e. at a given frequency) have been generally described for a variety of medical uses ranging from penile stimulation (U.S. Pat. No. 6,027,444), gum massage (U.S. Pat. No. 3,664,331), fingertip massage (U.S. Pat. No. 2,181,282, U.S. Pat. No. 1,498,680), assisting the diffusion of hair solutions into the scalp of a user (U.S. Pat. No. 5,830,177), eliminating mucus from the lung (U.S. Pat. No. 5,453,081), and for treatment of scoliosis of the spine (U.S. Pat. No. 6,082,365). These devices have not been optimally combined however, with a high powered vibration source (i.e. one adapted to emit a high displacement amplitude while under load) and an optimized attachment interface (i.e. enabling concentrated delivery of vibration localized to a selected body surface), to enable an effective, penetrative vibration delivery system suitable for treatment of acute vascular occlusions, which are often deeply situated within the human body.
Harris et al. in U.S. patent application Ser. No. 2002/0161315 A1 discloses a low frequency hand held percussive massager of indeterminate power (which purportedly enables at least marginal levels of force or intensity emission control), comprising a first vibratory massage element mounted to one side of the massage body and a pair of percussive “nodes” mounted to the opposite side. While of potential use to the current specification, the disclosed massager is not ideal as the placement and necessary operation of a vibratory element in diametric opposition to the percussive nodes is energy inefficient, and is inexpedient for use as it makes the device difficult to apply with significant engagement force by the hands of an operator. Furthermore the disclosed massager does not allow for the particular selection of variable stroke length or wave-shape control, which may be advantageous in a controlled research or clinical setting wherein definable, variable, and reproducible percussive stimuli may be desired.
High powered low frequency oscillation devices operable under load with moduable vibratory wave forms (including selectable intensity and even wave shape) are known to industry, but have found no common use in direct human contact for application to selected body surfaces, hence the oscillations imparted would be either indirect and dissipated, or fundamentally unsafe to apply. Examples of such vibration sources consist of: Aura Bass Shakers, Clark Synthesis Tactile Sound Transducers, industrial linear motors, speakers (i.e. voice coils—“woofers”), and pile drivers.
There has also been little focus In the area of directing or confirming the penetration levels of low frequency vibration (or percussion) to an invasively located target in a patient, via an imaging or monitoring technique.
Japanese Pat. No. JP 4156823 to Takishima et al. discloses a miniaturized accelerometer disposed on a transesophageal lead for monitoring penetration levels of externally imparted cardiac phased modulated vibration to the heart, to facilitate the diagnosis and treatment of heart failure. The requirement of an invasive step of introducing a transesophageal probe to enable vibration monitoring and targeting is not ideal (nor preferred) in emergency settings.
U.S. Pat. No. 6,068,596 to Weth et al. discloses an ultrasonic shock wave emission device coupled to an ultrasonic imaging probe to focus and direct ultrasonic shock waves to internalized neural clusters in chronic pain management. The '596 patent is not directed towards treatment of thromboses or acute vascular occlusions, and the resulting “pulsed” waves (which are only emitted once every couple of minutes) are in the ultrasonic range hence are of low amplitude and must be focused to yield a significant internal effect. Furthermore the ultrasonic imaging probe is not utilized to emit the therapeutic ultrasonic shock waves, hence an optimal acoustic (or penetration) delivery window through the overlying body surface is not established.
U.S. Pat. No. 5,919,139 to Lin discloses a low amplitude (designed for “gentle percussive hitting or vibrating”) sonic vibration source mounted side by side to an ultrasonic imaging transducer for diagnostic purposes, which enables visualization of the invasive target vibrated. This device is not designed for therapy, and is inexpedient for use (prospectively) in the location and disruption of tissue targets, as the sonic vibration source is not advantageously placed in the same position as the ultrasonic imaging probe upon the body surface, such as to conveniently enable an operator direct visualization and targeting of vibration through an optimized sonic penetration window proximate the vascular target.
As can be seen from above, there is an ongoing need to optimize a noninvasive system for the treatment of vascular ischemia and infarction by drug therapy and/or transcutaneously delivered mechanically therapeutic techniques. The prior art has failed to provide a simple to use, noninvasive mechanical method and apparatus that reliably ensures sufficient penetration to the culprit vessels and sites of vascular thromboses (in particular to the deeply situated vessels within the thoracic cavity such as the coronary arteries, or to the acoustically shielded vessels within the highly attenuating cranium such as the cerebral arteries) to ensure an adequate agitative and disruptive therapeutic effect in emergency cases. Furthermore, none of the prior arts have successfully integrated a systemically delivered drug therapy system, and/or the optional use of a practical noninvasive imaging system for targeting therapy, to optimally enable such an apparatus.
There is accordingly a need for an effective and easy to apply emergency response system in the application of noninvasive, therapeutic mechanical energy to the human body for the treatment of acute vascular occlusions such as in heart attack and acute ischemic (embolic) stroke. The system should be optionally portable to enable reaching a victim in the field, employable with drugs, and preferably adaptable to suit the expertise of an operator (i.e. with the optional incorporation of a practical and convenient imaging system) whose skill level and experience (and thereby preferred clinical approach) may vary markedly.